Research report
Expression of TMEFF1 mRNA in the mouse central nervous system: precise examination and comparative studies of TMEFF1 and TMEFF2

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Abstract

TMEFF1 and TMEFF2 are putative transmembrane proteins comprised of one epidermal growth factor (EGF)-like domain and two follistatin-like domains. Both TMEFF1 and TMEFF2 are predominantly expressed in the brain. We previously demonstrated that recombinant TMEFF2 protein can promote survival of neurons in primary culture and determined expression sites of TMEFF2 mRNA in the mouse central nervous system. To extend our understanding of TMEFF protein functions, we compared precise sites of expression of TMEFF1 and TMEFF2 mRNA using in situ hybridization analysis. Although both TMEFF genes are widely expressed in the brain, they exhibit different patterns of expression. TMEFF1 showed comparatively higher signals in the pyramidal cells of fifth layer of the cerebral neocortex, CA3, CA1 and subiculum regions of the hippocampus, locus coeruleus, and dentate cerebellar nucleus. In contrast, TMEFF2 is highly expressed in the medial habenular, CA2, CA3 and dentate gyrus region of the hippocampus, corpus callosum, cerebellar cortex and cranial nerve nuclei (III, IV, VII, X, XII). The results presented here indicate that expression of TMEFF1 and TMEFF2 are regulated differently and that they play region-specific roles in the central nervous system.

Introduction

TMEFF1 (‘Transmembrane protein with EGF-like and two follistatin-like domains 1’) was first identified in Xenopus laevis as X7365, a novel transmembrane protein containing a signal peptide, two follistatin modules, an EGF-like domain and a short cytoplasmic region [5]. The function of TMEFF1 is largely unknown, although its expression patterns have been characterized in Xenopus laevis, and a human ortholog has been cloned and mapped to human chromosome 9q31 [6].

Previously, we cloned a paralogous gene, TMEFF2 (also called tomoregulin [15]), and investigated precise expression sites and function in mammalian organisms. Northern-blot analysis showed that TMEFF2 is predominantly expressed in the both human and mouse brain. In situ hybridization analysis of mouse tissue also revealed expression throughout the brain, specifically in various types of neurons and glial cells. Furthermore, we demonstrated that a recombinant protein containing the putative extracellular domain of TMEFF2 promoted survival of neurons in primary culture [10]. The similarity between TMEFF1 and TMEFF2 suggests that the two proteins share similar functions. To better understand TMEFF functions, we have investigated the precise localization of TMEFF1 mRNA in the mouse central nervous system.

Section snippets

Probe preparation

Mouse TMEFF1 cDNA sequences are registered as overlapped ESTs in GenBank (accession numbers AA023493 and AA020026). Mouse TMEFF1 cDNA was amplified from mouse brain Marathon-Ready™ cDNA (Clontech) by PCR using the primer sequences 5′-AGAGGCAAGAGCAACTGCTC-3′ (P1) and 5′-TAGGAACTCCCGTCGGAAGC-3′ (P2). These P1 and P2 primers were designed based on the AA023493 and AA020026 sequences, respectively. The expected product size is 458 bp, corresponding to a segment (nucleotides 94 to 551) of a recently

Northern-blot analysis

Northern-blot analysis of mouse tissues showed that, like TMEFF2, TMEFF1 mRNA (2.9 kb, major band; 2.2 kb, minor band) is expressed predominantly in the brain [10]. High levels of TMEFF1 (2.9 kb, major band; 1.7 kb, minor band) expression were also detected in the testis, and moderate expression was observed in the lung and heart (Fig. 1 ). However, the predominant expression in the brain implicates involvement of TMEFF1 in the central nervous system.

Gross examination of TMEFF1 expression sites

Distribution of TMEFF1 mRNA was examined

Discussion

TMEFF1 and TMEFF2 are novel members of the EGF-like protein family; both proteins contain two follistatin-like domains and a single EGF-like domain, and are structurally unique within this family. Various neurotrophic growth factors and neural proteoglycans, including neuregulins [3], [4], [9], [11], [17], agrin [1], [2], [8], [14], neurocan [12] and brevican [16] have EGF-like domains. Notably, agrin, which plays a key role in the aggregation of acetylcholine receptors during synaptogenesis in

Acknowledgements

We thank Drs E. Kondo and H. Tsujino for help with the technical instruction and T. Iwanaga and M. Okano for technical assistance.

References (17)

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